Vasopressin is one of the major hormones involved in body fluid homeostasis and cardiovascular regulation. It is released into peripheral circulation by neurosecretory neurons located in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. Changes in blood pressure, plasma volume, osmolality and the concentration of circulating hormones all influence the activity of vasopressin neurons in the SON and PVN by activating specific pathways in the fully described. During essential hypertension (Robertson & Ganguly, 1986) AND pregnancy (Lindheimer et al., 1995) the regulation of vasopressin release by these pathways is reset. The long term goal of my research program is to determine the neural mechanisms that allow for this type of resetting in the neural control of vasopressin release. Before we can begin to determine these mechanisms on a cellular level, several of the neural system involved in the regulation of vasopressin release need to be defined. These studies will focus on neural pathways that bring arterial and cardiopulmonary information to the SON. The experiments described in this proposal are necessary steps toward reaching my long term career goals. Receiving this award would allow me to devote more time to my research program to conduct these experiments and to establish more cellularly oriented approaches in my laboratory. The ability to use in vitro approaches to study central pathways involved in the regulation of vasopressin release will be critical to determining the cellular mechanisms involved in their alterations by pregnancy and hypertension. The Department of Physiology and the Dalton Cardiovascular Research Center at the University of Missouri both support this application and provide an opportunity to establish and independent laboratory in a supportive collaborative environment. There is no better environment for the continued development of my research career. The specific aims of this proposal involve determining the pathways by which arterial baroreceptors and cardiopulmonary receptors regulate the activity of SON neurons. Ares in the central nervous system that are activated by cardiopulmonary afferents will be identified using volume expansion in unanesthetized rats. The role of the cardiopulmonary receptors in this response will be determine by acutely inactivating these receptors with pericardial injections of 2% procainamide. The results of these studies will be used as the basis for electrophysiological studies involving extracellular recording from characterized vasopressin and oxytocin neurons in the SON. Our earlier work has the SON. Preliminary data suggest that the locus coeruleus (LC) and perinuclear zone of the supraoptic nucleus (PNZ) may participate in both the baroreceptor-mediated inhibition and the cardiopulmonary receptor-mediated inhibition of vasopressin neurons in the SON. The role of the LC, the DBB and the PNZ in these responses will be tested by lesioning them with ibotenic acid. Future experiments will focus on determining the rest of the components of these two pathways and describing their neuropharmacology. These experiments will determine critical components of the pathways that allow the cardiovascular system to regulate the central nervous system.